What is the main goal for immunosuppressive therapy?
To prevent acute reactions to tissue transplants.
Also used to treat auto immune diseases
Most non selectively inhibit immune system components
What is the usual course of immunosuppressant therapy?
Intensive induction therapy for prophylaxis (usually antibodies)
Then Maintenance therapy with calcineurin inhibitors, antimetabolites and steroids
What are the calcineurin inhibitors?
Cyclosporine and Tacrolimus
What is the mTOR inhibitor?
What are the categories of immunosuppressants?
What is cyclosporine and how does it work?
A calcineurin inhibitor immunosuppressant.
Preferentially suppresses cell mediated immunity by binding to cyclophilin of T Cells. This complex inhibits calcineurin phosphatase which prevents dephosphorylation of NF-AT which normally activated transcription of IL-2 genes
reduces function of T cells
Metabolized by P450 so if given with p450 inhibitor it will be at higher levels
What are the common clinical uses for cyclosporine?
Big drug for prevention of organ rejection- Kidney, liver, and heart
Also used for rheumatoid arthritis and psoriasis
Used as a drop in sever eye dryness
Often administered with steroids
What are the toxicities of cyclosporine?
NephrotoxicIt can also induce hypertension, hyperlipidemia, and hirsutism. Gingival hyperplasia
What is Tacrolimus(FK506)?
A calcineurin inhibitor that is 10-100x more potent than cyclosporine with less pronounced side effects
Binds to immunophilin FKBP-12 and the complex binds calcineurin and blocks its phosphatase activity
Standard prophylactic for graft vs host disease (combined with methotrexate or mycophenolate)
What are the common clinical uses and toxicities for Tacrolimus?
Used mainly in liver and kidney transplant patients but can also be used in heart and lung transplantation
Used as an ointment for atopic dermatitis and psoriasis
Tox: Nephrotoxic, Neurotoxic, and causes diabetes
What is Sirolimus?
An immunosuppressant of the mTOR inhibiting class.
Works by binding FKBP-12(like Tacrolimus) the complex then blocks mTOR action which is needed for the cell to progress through G1 so there is no proliferation.
Also inhibits several T cell kinases/phosphatases preventing the transmission of signals that lead to cycle progression
What are the effects of Sirolimus therapy?
Decreases the RESPONSE to IL-2
prevents B cell differentiation into plasma cells-> lowering antibodies
Affects second phase of T lymphocyte activation (signal transduction and clonal proliferation
(cyclosporine and tacrolimus affect 1st phase- activation)
What are the advantages of Sacrolimus over calcineurin inhibitors?
Used to inhibit re stenosing of cardiac vessels by reducing proliferation of endothelial cells- SRL coated stent used to do this
What are the adverse efffects of Sirolimus use?
Hyperlipidemia, myelosuppression, hepatotoxicity, and slow wound healing
What are the antiproliferative/antimetabolite immunosuppressants?
What is methotrexate used for?
Autoimmune disease dreatment and to help treat against transplant rejection.
folic acid analogue- inhibits DHFR
What is Azathioprine?
An immunosuppressive cytotoxic agent. Used to control transplant rejection and to treat autoimmune disease.
It is cleaved wit 6-mercaptopurine which acts as a purine analogue inhibiting DNA Synthesis
Affects Cell mediated and humoral immunity since it prevents proliferation of lymphocytes in the immune response.
How is 6-MP metabolized?
80+% is metabolized by Xanthine oxidase to 6-thiouracil. The rest by TPMT and HPRT
Allopurinol is an XO blocker so it can increast levels of 6-MP increasing toxicity. Reduce dose to 1/4-1/3 if giving with allopurinol
What is Mycophenolate?
An immunosuppressant that has lowered the incidence of acute rejection- often used in place of azathioprine b/c of less marrow suppression, less infection, and better results.
Works by blocking inosine monophosphate dehydrogenase which is used to synthesize guanine in B and T lypmhocytes
Can be used alone for kidney and liver transplants
Steroid sparing agent in immune mediated responses like psoriasis and lupis nephritis
What is Leflunomide?
An inhibitor of pyrimidine synthesis used to treat rheumatoid and in prevention of organ rejection.
Orally available with a long half life of its active metabolite.
Toxicity: renal impairment and liver damage
What is cyclophosphamide?
Very effective immunosuppressant
can be used for autoimmune disease like SLE or autoimmune hemolytic anemia
Larger doses to treat transplant rejection
What are the antibodies used in immunosuppression?
Anti Thymocyte Globulin
T cell receptor directed antibodies- muromonab- CD3 or OKT3
IL-2 receptor directed antibodies- Daclizumab or Basiliximab
these block t cell surface signaling
What is anti thymocyte globulin?
A polyclonal antibody used in prevention/treatment of acute organ rejection
Also used in treatment of aplastic anemia in patients who can't have BM transplant
Starting to be replaced by anti IL-2R antibodies Basiliximab and Daclizumab b/c they cause less cytokine release
What is Rh(D) Globulin?
Human IgG against Rh(d) antigen of the red cell. Given to Rh negative mothers pregnant with Rh+ babies.
The Ab will bind to the baby Rh antigen blocking the mother's immune system from spotting them and attacking.
DO NOT give to Rh + mothers or newborns
Can also be used to prevent sensitization
What are monoclonal antibodies?
Abs directed at a single toxin- used in diagnostic tests, immuneosuppression, and cancer treatment
Human mAbs have reduced serum sickness
Less chance of eliciting human anti mous antibodies
What is Muromunab CD3(OKT3)?
Murine monoclonal antibody that binds CD3 receptor on human T lymphocytes- blocking them from making the signal for proliferation
Used to treat acute rejection of kidney, liver, and heart transplant
Cause severe cytokine release syndrome and CNS disturbances
Steroids can be used to reduce the symptoms of cytokine release
What are Basiliximab and Daclizumab?
Basiliximab is a chimeric mAb against CD 25 on Tcells (IL2 R alpha chain) thus blocking the activation of T lymphocytes by IL-2
Daclizumab is humanized mAb against Tcell CD25
Both used for prophylaxis against organ rejection
Well tolerated with less risk of opportunistic infections and lymphomas
What is Bevacuzimab?
mAb that blocks VEGF from binding it's receptoron endothelial cells
Approved for first line treatment of metastatic colon cancer
What is infliximab?
mAb to TNF alpha receptor used to treat RA and chrons
What is Omalizumab?
mAb to IGE used to treat bronchial asthma
What is Palivizumab?
mAb that blocks RSV fusion protein.
Used as prophylaxis to RSV
What is Rituximab?
mAb to CD20 on B cells
Used to treat NHL
What are the effects of glucocorticoids in the immune system?
Both immunosuppressants and anti inflammatories
Suppression of cell mediated immunity by blocking genes for cytokines 1-6, 8, and TNF-1 reducing T cell proliferation
Humoral immunity also suppressed by causing Bcells to express lesser IL-2R diminishing both Bcell clone expansion and antibody synthesis
Used to treat rejection, autoimmune diseases, and to limit allergic reactions that occur with muromonab and other Abs
What is Aldesleukin?
Recombinant IL-2 that promotes the production of cytotoxic T lymphocytes and activates NK cells.
Used for Renal cell carcinoma and malignant melanoma.
What is BCG (Bacille Calmette-Guerin)?
Immunostimulant used in the prevention and treatment of superficial bladder cancer- given intravesicularly
Live attenuated form of mycobacterium bovis. When administered causes a local immune response that has anti tumor activity. helps decrease the need for cyctectomy
What are the interferons that are used as immunomodulators?
Interferon-a-2a used in CML, malignant melanoma, and hep B and C
Interferon-B-1b- used to treat multiple sclerosis
What is the best treatment for Autoimmune Thrombocytopenic purpura?
What are the high efficacy diuretics?
Inhibitors of Na K 2Cl co transport in the ascending loop of henle.
Furosemide is the prototype- has vasodilator action
Torsemide- a longer acting with less K wasting
Bumetanide, and Ethacrynic acid
What is the mechanism that causes hyperkalemia?
when sodium absorption is blocked it makes it further down the tube to the collecting duct. Here there will be larger Na absorbption which will also cause increased K+ and H+ secretion.
If you block the Na channel in the collecting duct you stop secretion of K+ and H+= potassium sparing
What are the medium efficacy diuretics?
Inhibitors of NA-Cl co transport
Chlorothiazide, Chlorthalidone, Metolazone, and Indapamide(thiazide like diuretic)